Children under two years of age, the elderly, and individuals with underlying disease are to great risk of developing pneumococcal otitis media, septicemia, meningitis, and pneumonia. Antibiotic prophylaxis and vaccination are the two major methods to treat and prevent invasive pneumococcal infections. However, the success of antibiotic treatments has been limited by the recent isolation of penicillin-or multi-drug resistant pneumococci. The current pneumococcal vaccine, a mixture of capsular polysaccharide of 23 most prevalent of possible 84 stereotypes, only elicits type-specific antibodies and can not provide protection against infection of other Streptococcus pneumoniae serotypes not used in the vaccine preparation. To control pneumococcal disease would require a new knowledge about the biology of S. pneumoniae. The long range goal of this investigation is to study how S. pneumoniae survives in infected animals where most of iron molecules are sequestered by iron-binding proteins, such as hemoglobin, transferrin, and lactoferrin. Iron limitation restricted the growth of S. pneumoniae and the limited growth could be restored by the addition of hemin or hemoglobin. Pneumococcal cells have a great ability to bind hemin. Several hemin binding proteins have been identified in the cell lysate of S. pneumoniae with the major species migrated as a molecular mass of 43 kDa. The specific aims of this proposal are employing genetic and immunological methods to seek answers to the following question: 1). What is the genetic determinant of 43-kDa hemin binding protein? 2). What roles does 43-kDa HBP play in the hemin acquisition of S. pneumoniae? 3) What roles does 43-kDa HBP play in S. pneumoniae infection in experimental animals? Results generated from the proposed studies not only will provide us with basic information about the iron acquisition of S. pneumoniae, but will allow us to gain insight into the pathogenic mechanism of S. pneumoniae disease. The knowledge obtained in this study will have practical applications as well in designing effective therapeutic strategy and agents for the control of pneumococcal disease.